In recent years, a pharmaceutical to inhibit a Na+-glucose cotransporter (SGLT) in the intestinal tract and kidney to reabsorb glucose (a Na+-glucose cotransporter inhibitor) has been demanded as an antidiabetic agent to rapidly normalize hyperglycemia and improve the energy balance in the body. Such a Na+-glucose cotransporter inhibitor has been expected as an excellent pharmaceutical for treating or preventing diabetes such as insulin-dependent diabetes (type 1 diabetes) and insulin-independent diabetes (type 2 diabetes), as well as diabetes-related diseases such as insulin-resistant diseases and obesity.
As compounds used as the Na+-glucose cotransporter inhibitor, phloridzin described in Welch, C. A. et al. (J. Natr., 1989, 119(11) 1698) and a synthetic O-glycoside described in Hongu, M. et al. (Chem. Pharm. Bull., 1998, 46(1) 22) and JP-A-11-21243 are known, for example. These compounds are reported to discharge excess blood glucose into urine and reduce the level of blood glucose by inhibiting a Na+-glucose cotransporter in the kidney.
However, since any of these compounds are an O-glycoside comprising an O-glucoside bond formed between glucose and an aglycon moiety, it has a problem that the hypoglycemic effect is disappeared due to hydrolysis of O-glucoside bond by glucosidase or the like in the small intestine when orally absorbed.
Phloretin, an aglycon moiety of phloridzin, is known to highly inhibit a facilitated diffusion-type glucose transporter. For example, it is reported that the cerebral glucose concentration decreases when phloretin is administered to the vein of a rat (e.g. Stroke, 1983, 14, 388). Phloretin is also known to inhibit a vitamin C transporter (Wang, Y. et al., Biochem. Biophys. Res. Commun., 2000, 267, 488–494).
Therefore, an attempt has been made to use a C-glycoside prepared by converting oxygen in the glucoside bond of the O-glycoside to carbon as the Na+-glucose cotransporter inhibitor.
For example, JP-A-2001-288178 (hereinafter referred to as Patent Document 1) describes that a compound of the following formula has the effect of inhibiting a Na+-glucose cotransporter and is useful as a treating agent or preventing agent for diabetes and a hypoglycemic agent.
wherein R1 represents H, OH, lower alkyl group, —O-lower alkyl group, or the like, R2 represents H, —COO-lower alkyl group, or the like, R5 represents —CH2OH, —CH2OCOO-lower alkyl group, or the like, A1 represents pyridine, furan, thiophene, quinoline, indole, or the like, n is 0, 1, 2, or 3, and m is 0 or 1 (See Patent Document 1 for further details on the symbols of the above formula).
In addition, the pamphlet of WO 01/27128 (hereinafter referred to Patent Document 2) describes that a compound of the following formula can be used as the Na+-glucose cotransporter inhibitor to treat obesity or type 2 diabetes.
wherein R1, R2, and R2a individually represent a hydrogen atom, OH, OR5, alkyl, CF3, OCHF2, OCHF3, or the like, R3 and R4 individually represent a hydrogen atom, OH, OR5a, —O-aryl, —O—CH2-aryl, alkyl, cycloalkyl, CF3, or the like, A represents O, S, NH, or (CH2)n, and n is 0, 1, 2, or 3 (See Patent Document 2 for further details on the symbols of the above formula).
As explained above, the C-glycoside is useful to a certain extent for treating diabetes due to the effect of inhibiting a Na+-glucose cotransporter. However, due to the recent rise in incidence of diabetes which is a lifestyle-related disease and could even be called a national disease, a compound having a chemical structure different from that of a known compound and showing the effect of inhibiting a Na+-glucose cotransporter more rapidly and more significantly has been increasingly desired for the clinical practice of diabetes treatment or the like.